The current initial approach to idiopathic nephrotic syndrome in children is a therapeutic trial of steroids and was based on data from 25 years ago, which showed that 80% of these patients have minimal-change disease and are steroid-sensitive (SS). The incidence of steroid resistance (SR) has increased significantly since that time. Better biomarkers are needed to facilitate appropriate choices of therapy, to avoid unnecessary toxicity, and to provide clues to the pathogenesis and prognosis of idiopathic nephrotic syndrome in childhood. We hypothesize that urine biomarkers, in the form of high-molecular-weight (HMW) and low-molecular-weight (LMW) proteins, are better predictors of the natural course, outcome, and the response to treatment of idiopathic nephrotic syndrome of childhood than total or intermediate-molecular-weight (IMW) proteins such as albumin. HMW proteinuria is associated with segmental sclerosis, while LMW proteinuria is associated with tubulointerstitial damage on renal biopsy. SR patients will be compared with patients with SS patients in a pilot cross-sectional, case-control study of nephrotic syndrome in childhood. We will identify at least 2 novel urinary protein biomarkers in the HMW range and 2 novel urinary protein biomarkers in the LMW range for SR using cutting-edge proteomics methodology. We will determine the mean and standard deviation of the excretion rate of novel and known urinary biomarkers in SR versus SS patients. In the R33 phase, we will conduct a prospective epidemiologic study of idiopathic nephrotic syndrome in children in order to define the prognostic value of the SR biomarkers identified in the R21 phase in a prospective study of children who first presented with nephrotic syndrome. We will conduct the R33 phase with member institutions of the Western Consortium for Pediatric Nephrology Clinical Trials Group. We will correlate the excretion rate of SR biomarkers to the extent of glomerular and tubulointerstitial fibrosis on renal biopsy, which will be measured by a novel quantitative computer imaging methodology. These biomarkers will be localized in the biopsy by immunohistochemistry and in-situ hybridization. The biomarkers identified will be tested for pathogenetic significance by determining the effect of overexpression or application of exogenous recombinant protein in podocyte, mesangial cell and proximal tubular cell. We believe that data from the current study will improve our diagnostic and therapeutic strategy and may provide clues to the pathogenetic significance of the identified biomarkers.